In addition to his written work, Callen was a leader and founder of activist organizations including The People with AIDS Coalition and the Community Research Initiative.

Callen remained a primary public figure in AIDS activism until he died at age 38 from AIDS-related complications of pulmonary Kaposi's sarcoma at Midway Hospital Medical Center in Los Angeles, California.

[2] In Love Doesn't Need a Reason the author, Jones, wrote that Michael Callen requested that Douglas Sadownick and Tim should be granted power of attorney over him.

In Surviving AIDS, Callen exposes what he calls the “propaganda of hopelessness”, arguing that public health officials and researchers are more interested in the dead than the living, ultimately largely ignoring long-term survivors.

After Low Life disbanded, Callen's solo album Purple Heart was released and quickly acclaimed as a staple of gay men's music.

[13] Additionally, Callen made cameo appearances in the films Philadelphia (1993) and Zero Patience (1993), in which he famously performed a song in falsetto as the fictitious "Miss HIV".

[4] In partnership with Oscar winner Peter Allen and Marsha Melamet, Callen wrote his most famous song, "Love Don't Need a Reason", commissioned by Larry Kramer for his play, The Normal Heart.